Harmine Plus Exendin-4 Enhances Remission of Recent-Onset Type 1 Diabetes Following Anti-CD3 Therapy
- 1City of Hope
Abstract
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic {beta}-cells. While anti-CD3 therapy can delay disease progression and preserve residual {beta}-cell function, disease reversal will likely require both immune modulation and {beta}-cell regeneration. We found that the combination of harmine and exendin-4 (H+E) reduced inflammation-induced human {beta}-cell apoptosis, suppressed cytokine signaling and immunogenicity pathways, and improved {beta}-cell function. Although H+E alone did not reverse diabetes in NOD mice, low-dose anti-CD3 followed by H+E normalized blood glucose, increased insulin levels, improved glucose tolerance, expanded {beta}-cell mass, and enhanced diabetes remission. These effects were associated with reduced pro-inflammatory T-cell responses, increased regulatory T cells, and greater expression of exhaustion-related T-cell markers, without broad lymphocyte depletion. Similar immunomodulatory effects were observed in activated human PBMCs. Transcriptomic analyses identified the lncRNA SNHG6 as a key mediator of H+E action; SNHG6 protected {beta}-cells from cytokine-induced stress, apoptosis, and immunogenicity. Together, these findings demonstrate that H+E promotes {beta}-cell recovery and resilience while reducing {beta}-cell immunogenicity, enabling remission of recent-onset T1D when combined with anti-CD3 therapy. SNHG6 emerges as a novel regulator of {beta}-cell protection during inflammation.
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BibTeX
@misc{lu2026harmine,
title = {{Harmine Plus Exendin-4 Enhances Remission of Recent-Onset Type 1 Diabetes Following Anti-CD3 Therapy}},
author = {G. Lu and R. Kang and M. Varela and E. Oh and Y. Li and J. Lee and L. Kebrom and J. Aldaco and J. Zhang and M. Wichman and M. Li and F. Kandeel and M. Qi and P. Wang and R. J. Devita and A. Pugliese and D. C. Thurmond and A. F. Stewart and A. Garcia-Ocana},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753317},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753317v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Harmine Plus Exendin-4 Enhances Remission of Recent-Onset Type 1 Diabetes Following Anti-CD3 Therapy
AU - G. Lu
AU - R. Kang
AU - M. Varela
AU - E. Oh
AU - Y. Li
AU - J. Lee
AU - L. Kebrom
AU - J. Aldaco
AU - J. Zhang
AU - M. Wichman
AU - M. Li
AU - F. Kandeel
AU - M. Qi
AU - P. Wang
AU - R. J. Devita
AU - A. Pugliese
AU - D. C. Thurmond
AU - A. F. Stewart
AU - A. Garcia-Ocana
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753317
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753317v1
AB - Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic {beta}-cells. While anti-CD3 therapy can delay disease progression and preserve residual {beta}-cell function, disease reversal will likely require both immune modulation and {beta}-cell regeneration. We found that the combination of harmine and exendin-4 (H+E) reduced inflammation-induced human {beta}-cell apoptosis, suppressed cytokine signaling and immunogenicity pathways, and improved {beta}-cell function. Although H+E alone did not reverse diabetes in NOD mice, low-dose anti-CD3 followed by H+E normalized blood glucose, increased insulin levels, improved glucose tolerance, expanded {beta}-cell mass, and enhanced diabetes remission. These effects were associated with reduced pro-inflammatory T-cell responses, increased regulatory T cells, and greater expression of exhaustion-related T-cell markers, without broad lymphocyte depletion. Similar immunomodulatory effects were observed in activated human PBMCs. Transcriptomic analyses identified the lncRNA SNHG6 as a key mediator of H+E action; SNHG6 protected {beta}-cells from cytokine-induced stress, apoptosis, and immunogenicity. Together, these findings demonstrate that H+E promotes {beta}-cell recovery and resilience while reducing {beta}-cell immunogenicity, enabling remission of recent-onset T1D when combined with anti-CD3 therapy. SNHG6 emerges as a novel regulator of {beta}-cell protection during inflammation.
ER -